This invention was funded in part by Grant Nos. CA 15898 and CA 13943 from the National Cancer Institute, National Institutes of Health.
This invention relates to a new class of cytotoxic liponucleotide analogs (sometimes abbreviated herein as CLNA) drugs having useful cytotoxic activity, to methods of preparing and using such drugs and to pharmaceutical compositions containing cytotoxically effective amounts of such drugs as a primary active ingredient.
Cancer can be considered as a group of diseases that can occur in any tissue, organ or system of the body. The causes of all cancers are not known, nor are there any reported major qualitative metabolic differences between cancer cells and host tissue cells of origin. Accordingly, cancer chemotherapy, unlike the chemotherapy of infectious diseases wherein the disease-causing organism itself offers a distinct metabolic or structural biologic target, has far more restrictive fundamental concepts on which to pattern therapeutic treatment.
Most known classes of anticancer drugs exert their action principally because of quantitative differences in metabolic rates of production or levels of certain nucleic acids, enzymes, proteins, hormones, metabolic intermediates, etc., rather than because of qualitative biologic differences between cancer cells and normal cells. Thus, anticancer drugs do not exhibit selective toxicity in the classical sense.
A number of anticancer nucleosides or bases have been described in the prior art. For example, cytosine arabinoside, 5-fluorouracil, 5-fluorodeoxyuracil, 6-mercaptopurine and thioguanine have become drugs currently used for the clinical treatment of cancer in human patients. In addition, preliminary clinical trials appear encouraging with respect to a dozen or more other drugs as have been reported by H. B. Wood, Jr. in "Drugs with Chemical Activity" and in "Some Unique Compounds in Development" published by the Drug Synthesis and Chemistry Branch, National Cancer Institute, January 1977, the contents of which are incorporated by reference herein. Literally scores of pyrimidines, purines, structurally related heterocyclic bases, nucleosides, etc., have been synthesized and demonstrated to possess high cytotoxic activity in cell culture and in a number of tumor-bearing animals; however, unfavorable therapeutic indexes have restricted the clinical use of this class of antimetabolites to relatively few antineoplastic drugs presently used for the chemotherapy of cancer.